Liver-resident CD8 T cells do not need Levy walks to be efficient killers

Abstract

Abstract Movement strategies by which antigen-specific CD8 T cells search for sites of infection are not fully understood. It was recently suggested that activated CD8 T cells, specific for Toxoplasma gondii, perform generalized Levy walks in murine brains; that is cells perform a local search and then displace randomly to distant locations. Several theoretical studies found that Levy walkers are an order of magnitude more efficient at finding rare targets than Brownian walkers. We investigated movement patterns of Plasmodium-specific liver-resident CD8 T cells using intravital microscopy. Based on the distribution of movement lengths Trm cells performed Brownian walks and yet displayed superdiffusive (Levy-like) behavior, i.e., on average they displaced further from the initial position than that predicted by the standard diffusion theory. Mapping out structure of liver sinusoids revealed that superdiffiusive nature of T cell walks in the liver is likely due to small branching angles of the sinusoids, instructing T cells to move directly. By simulating T cells moving as Brownian or Levy walkers in free space or physiologically constrained liver sinusoids we showed that structure may override the intrinsic pattern of cell movement. Interestingly, while Levy walkers indeed required less time than Brownian walkers to find rare targets when search was done in space with no constrains, on average, this advantage disappeared when search was done in the liver. Our results, thus, suggest that observed patterns of movement of T cells in the liver are likely to arise as a combination of cell-intrinsic search patterns and environmental constrains, and that evolutionary benefits of Levy walks may be limited in biologically-relevant environments.